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Updated: Feb 5, 2026

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

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Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer

Denise Treue1, Michael Bockmayr1,2, Albrecht Stenzinger3,4,5

  • 1Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.

International Journal of Cancer
|September 6, 2018
PubMed

Insights

This study identifies key proteins (HSPB1, DBNL, AKT1) that overcome EGFR-inhibitor resistance in lung cancer. Targeting these proteins shows potent anti-cancer effects, offering new combination therapy strategies for precision medicine.

Area of Science:

  • Oncology
  • Systems Biology
  • Genomics

Background:

  • Precision medicine in cancer relies on understanding genetic mutations.
  • The functional impact of rare mutations and mutation combinations remains largely unknown.
  • EGFR-mutated non-small cell lung cancer (NSCLC) often develops resistance to targeted therapies.

Purpose of the Study:

  • To identify functionally relevant molecular alterations driving resistance to targeted therapy in EGFR-mutated NSCLC.
  • To reduce the complexity of genetic events and identify key phosphoproteins involved in resistance.
  • To propose novel therapeutic targets and combination strategies.

Main Methods:

  • Integrated systems analysis combining whole exome sequencing, time-course phosphoproteomics, and computational modeling.
  • Complexity reduction from over 2,000 genetic events to 44 phosphoproteins and 35 related genetic alterations.
  • In vitro drug testing (single and combination) against identified phosphoproteins.

Main Results:

  • Identified 44 key phosphoproteins and 35 associated genetic alterations mediating resistance.
  • Targeting HSPB1, DBNL, and AKT1 demonstrated potent antiproliferative effects.
  • These targeted therapies effectively overcame resistance to EGFR-inhibitory therapy.

Conclusions:

  • The developed systems analysis approach can identify functionally relevant molecular aberrations beyond simple mutational profiling.
  • Targeting specific phosphoproteins like HSPB1, DBNL, and AKT1 offers a promising strategy to overcome therapeutic resistance in NSCLC.
  • This approach can guide the development of effective combination therapies for various cancers.
Keywords:
drug resistancelung cancerproteomicsystem biology

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